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Yoshihiko Sugihara,1 Shigehito Ikushima,1 Mika Miyake,1 Takayoshi Kirisako,2 Yukihiro Yada,3 Daisuke Fujiwara2 1Research Laboratories for Health Science and Food Technologies, 2Central Laboratories for Key Technologies, Research and Development Division, Kirin Company, Limited, Yokohama, 3Doctorate Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Japan Purpose: The present study examined the effect of ingestion of Koji extract containing 14-dehydroergosterol (14-DHE), prepared from Aspergillus kawachii NBRC4308, on improvement of skin conditions among healthy volunteers. Subjects and methods: In a randomized, double-blind, placebo-controlled, parallel-group study, 70 healthy adult women who felt that their skin was dry ingested either a placebo dietary supplement or Koji extract (200 mg/day) supplement containing 0.1% 14-DHE for 12 weeks. Throughout the treatment period and for 4 weeks afterward, objective indicators – including moisture content of the stratum corneum, trans-epidermal water loss (TEWL), and skin wrinkles – were evaluated; in addition, the subjects answered a questionnaire on their skin conditions with ratings on a visual analog scale. Statistical analysis was conducted on the basis of differences from baseline scores. Results: Compared with the placebo group, the Koji extract group showed significantly increased forearm moisture at 4, 8, and 16 weeks (p < 0.05 on unpaired t-test). The questionnaire survey showed a marked improvement in skin conditions, particularly crow’s feet, in the Koji extract group versus the placebo group at 8 weeks (p < 0.05 by unpaired t-test). Furthermore, the Koji extract group showed a trend (p < 0.10) toward improvement in skin moisture (at 4 weeks), dryness around the eyes/mouth (at 4 weeks), and overall skin condition (at 8 weeks) versus the placebo group. Conclusion: Ingestion of Koji extract containing 14-DHE was demonstrated to have positive effects toward improving skin conditions – in particular, on increasing skin moisture in the stratum corneum. Keywords: 14-dehydroergosterol, Aspergillus, Koji, skin, skin moisture, TEWL

Introduction. Antimicrobial resistance (AMR) is a growing global concern. Clonal lineages of CTX-M β-lactamase-producing Escherichia coli (CTXE) and quinolone-resistant E. coli (QREC) were disseminated among the deer population in a famous tourist destination (Nara Park; NP) in Japan. Hypothesis/gap statement. The molecular characteristics of CTXE or QREC isolates, which could pose a threat to public health, have not been elucidated. Aim. This study aimed to characterize the genetic traits of CTXE and QREC isolates derived from NP deer and compare them with lineages prevalent worldwide. Methodology. Sixteen CTXE and three QREC isolates recovered from NP deer faeces between 2018 and 2020 were analysed using whole-genome sequencing (WGS). For endemic lineages, phylogenetic trees were constructed against the isolates registered in the EnteroBase database using the core genome SNP scheme. Results. The most prevalent lineage in NP deer was ST3580. Several pandemic lineages, such as sequence type (ST) 38, ST58 and ST117, were included. The QREC lineages prevalent among deer were designated as extra-intestinal pathogenic E. coli or uropathogenic E. coli (UPEC). Thirteen of the 24 antimicrobial resistance genes (ARGs) were considered high-risk ARG families. Chromosomal integration of bla CTX-M-15 was observed in all plasmid-negative isolates. Phylogenetic analysis suggested relationships between NP isolates and isolates sourced from the environment or poultry. Conclusion. ST3580 has a high potential for clonal dissemination. Furthermore, multiple clinically relevant lineages of CTXE and QREC are endemic in NP deer; however, they could be less virulent than isolates belonging to the same lineages, which could cause severe infectious diseases. Further studies are required to investigate the relationship between chromosomal integration of plasmid-encoded genes and the stable propagation of AMR bacteria in wildlife and the environment., Competing Interests: The authors declare that that there are no conflicts of interest., (Copyright © 2024 The Authors.)

Osimertinib is used as the first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, early dose reduction is often required due to adverse events (AEs). This study aimed to evaluate the effect of early dose reduction of osimertinib on efficacy and safety. This was a retrospective study including patients with EGFR-mutated NSCLC who were started on osimertinib as the first-line therapy between August 2018 and December 2021. Patients whose doses were reduced to less than 80 mg/day within 6 months of osimertinib initiation or started at 40 mg/day were defined as the dose reduction group. The primary endpoint was progression-free survival (PFS). Factors affecting PFS were explored using the Cox proportional hazards model. A total of 85 patients were included in this study. No significant differences in patient characteristics were observed between the dose reduction (n = 25) and standard dose groups (n = 60). The median PFS in the dose reduction group was significantly prolonged compared with that in the standard dose group (26.0 months vs. 12.0 months, p = 0.03). Multivariable analysis of 84 patients, excluding a patient with unknown brain metastasis, revealed that EGFR exon 21 L858R mutation, malignant pleural effusion or pleural metastasis, liver metastasis, and dose reduction within 6 months were independent factors affecting PFS. Early dose reduction of osimertinib is an effective therapeutic strategy for prolonging PFS in patients with EGFR-mutated NSCLC., (© 2024. The Author(s).)

Transmission of antimicrobial-resistant bacteria among humans, animals, and the environment is a growing concern worldwide. The distribution of an international high-risk fluoroquinolone-resistant Escherichia coli clone, ST131, has been documented in clinical settings. However, the transmission of ST131 from humans to surrounding environments remains poorly elucidated. To comprehend the current situation and identify the source of ST131 in nature, we analyzed the genetic features of ST131 isolates from the aquatic environment (lake/river water) and wildlife (fox, raccoon, raccoon dog, and deer) and compared them with the features of isolates from humans in Japan using accessory and core genome single nucleotide polymorphism (SNP) analyses. We identified ST131 isolates belonging to the same phylotype and genome clusters (four of eight clusters were concomitant) with low SNP distance between the human isolates and those from the aquatic environment and wildlife. These findings warn of ST131 transmission between humans and the surrounding environment in Japan., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Wildlife in urban areas have the potential to disseminate antimicrobial-resistant bacteria (ARB) across a wider environment. Using antimicrobial-supplemented agar plates, we isolated extended-spectrum β-lactamase-producing Escherichia coli (EEC) and quinolone-resistant E. coli (QREC) from 144, 23, and 30 deer feces from Nara Park (NP), rural area neighboring NP (RA), and Mt. Odaigahara (MO), respectively. In NP and RA, the prevalence of EEC was 24.3 and 4.3%, respectively; that of QREC was 11.1 and 17.4%, respectively. Neither EEC nor QREC were detected in MO. The pulsotypes of EEC and QREC isolates differed between NP and RA. Our study suggests that deer of the Nara Prefecture are potential carriers of ARB, but long-distance dissemination is unlikely due to limited deer movement.

Background/aim: Osimertinib is a key drug for treating epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). Genetic differences may be associated to adverse events (AEs) induced by osimertinib. This retrospective observational multicenter study evaluated the association of genotypes, including STAT3 -1697C>G, CYP3A5 6986A>G, and ABCG2 421C>A, with the incidence of osimertinib-induced AEs in patients with EGFR mutation-positive NSCLC., Patients and Methods: A total of 85 patients treated with osimertinib (Institution A: 33 patients, Institution B: 52 patients) were enrolled in the study. Single nucleotide polymorphisms were determined by real-time PCR, and the incidence of AEs was compared for each genotype., Results: Paronychia incidence was 59% for the CC genotype, 19% for the CG genotype, and 19% for the GG genotype at STAT3 -1697C>G. A genotype-related trend was observed (Cochran-Armitage test, p=0.009). Multivariate analysis showed that the CC genotype at STAT3 -1697C>G and female sex were significant independent factors associated with paronychia [odds ratio (OR)=6.41, 95% confidence interval (CI)=1.94-21.20 and OR=3.40, 95%CI=1.03-11.22, respectively]. The incidence of diarrhea was 53% for the CC genotype, 30% for the AC genotype, and 29% for the AA genotype at ABCG2 421C>A, and a genotype-related trend was observed (p=0.048). However, the CC genotype at ABCG2 421C>A was not a significant independent factor associated with diarrhea in multivariate analysis. No significant associations were detected between other polymorphisms and the incidence of AEs., Conclusion: STAT3 -1697C>G may be a novel risk factor for osimertinib-induced paronychia in patients with NSCLC., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Clinical evidence on the increased efficacy of sequential epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) is limited. This study aimed to compare the efficacy of upfront use of first-/second-generation TKI followed by osimertinib with upfront osimertinib therapy for each representative EGFR mutation in Japanese patients with NSCLC. Patients with EGFR-mutated NSCLC were classified into two groups: first-/second-generation TKI followed by osimertinib (sequential TKI group) and upfront osimertinib groups. The total time to treatment failure (TTF) of TKI therapies, progression-free survival (PFS), and overall survival (OS) were retrospectively evaluated. Of the 74 patients included in the analysis, 38 and 34 patients had exon 19 deletion and L858R, respectively, and other two patients had minor mutations. The sequential TKI group had a significantly longer TTF than the upfront osimertinib group in overall patients (33.2 vs. 11.2 months; p = 0.007) and in the subgroup of exon 19 deletion (36.7 vs. 10.0 months; p = 0.004), but not in the subgroup of L858R (22.6 vs. 15.6 months; p = 0.37). The similar tendency was observed in PFS. OS of the sequential TKI group was significantly longer compared with the upfront osimertinib group in overall patients, the subgroup of exon 19 deletion, and the subgroup of L858R. The upfront use of first-/second-generation TKI followed by osimertinib is one of the feasible and effective strategies in Japanese patients with EGFR-mutated NSCLC, especially in patients with exon 19 deletion.

Monitoring the mortality of wildlife provides basic demographic information to support management plan preparation. The utility of mortality records for conservation measures was investigated in the Japanese serow, focusing on temporal trends and spatial distribution. Using the mortality records of Japanese serow from 2006 to 2018 in Gifu prefecture, cause-specific mortality was categorized into five groups (disease, accident, vehicle collision, parapoxvirus infection, and unknown), and the sex ratios were examined. A state space model was used to analyze the time series for the monthly mortalities, and kernel estimation was used for the spatial distribution of the parapoxvirus infection. Land cover type around the detection point was also reported. Disease, accident, and vehicle collision mortality were similar, and 30% of mortality was of anthropogenic origin. The number of mortality records for males was higher, and the larger home range of males could account for this. The state space model showed moderate increases in monthly mortalities over time and a seasonal variation with the highest level in spring and lowest in winter. Land cover analysis demonstrated a temporal increase in the proportion of human settlement areas, suggesting the change of the Japanese serow habitat. The proximity of Japanese serow to human settlements contributed to increase in mortality records. The point pattern analysis indicated spatial clustering for parapoxvirus infection in the area where an epidemic had occurred in the past. Several measures are recommended; however, mortality records can help develop improved conservation plan.

The emergence and dissemination of resistance to clinically important antimicrobials in wild animals is of great concern. The aim of our study was to reveal the prevalence and intraspecies dissemination of quinolone-resistant Escherichia coli (QREC) in sika deer (Cervus nippon) in Nara Park, a famous tourist spot in Japan. Fecal samples were collected from 59 wild deer in Nara Park between July and October 2018. We isolated QREC using deoxycholate-hydrogen sulfide-lactose agar containing nalidixic acid and subjected it to antimicrobial susceptibility testing. The mutations in the quinolone resistance-determining region (QRDR) of the gyrA and parC genes of the isolates were analyzed and fragment patterns of genomic DNA were compared by pulsed-field gel electrophoresis (PFGE). A total of 105 QREC isolates were obtained from 41 deer (70%). All isolates had mutations within the QRDR. Other than quinolone resistance, QREC isolates also showed resistance to various other antimicrobial agents. The QREC isolates were classified into 15 PFGE clusters, of which seven were observed in multiple deer. Our results suggest clonal transmission of QREC in a high-density deer population. Spread of QREC in deer inhabiting a tourist location could have potential impact on public health., (© Wildlife Disease Association 2021.)

In this retrospective study, we investigated vascular abnormalities in sarcoidosis using fluorescein gonioangiography (FGA) to detect angle neovascularization (ANV), fundus fluorescein angiography (FFA), and pathological specimens from the aspects of microangiopathy. In 57 sarcoidosis patients, clinical data was reviewed by dividing the cases into three groups (Group I: histologically diagnosed; Group II: positive bilateral hilar lymphadenopathy (BHL); Group III: negative BHL). The FFA, FGA, and pathological examination data in the autopsy eyes and trabeculectomy specimens were investigated. FGA and FFA detected ANV (91%) and nodule-associated abnormalities (87%), respectively. No intraocular pressure (IOP) elevation was observed after continuous topical betamethasone, except in the steroid responder group. Maximum IOP had significant correlation with nodules in the angle ( p = 0.02696) and visual field defect ( p = 0.0151). Granulomas adjacent to blood vessels, including the Schlemm's canal, and thickening of the retinal blood vessel wall caused occlusion of those vessels. Photocoagulation was required for retinal tears (14%) and the retinal blood vessel occlusion (7%). Suppression of IOP elevation via continuous topical betamethasone may be important to avoid irreversible outflow-route changes and optic-nerve damage, and the concept of microangiopathy in ocular sarcoidosis may be important for understanding the proper treatment of serious complications.

Retail meats are one of the main routes for spreading antimicrobial-resistant bacteria (ARB) from livestock to humans through the food chain. In African countries, retail meats are often sold at roadside butcheries without chilling or refrigeration. Retail meats in those butcheries are suspected to be contaminated by ARB, but it was not clear. In this study, we tested for the presence of antimicrobial-resistant Escherichia coli from retail meats ( n  = 64) from roadside butcheries in Kampala, Uganda. The meat surfaces were swabbed and inoculated on PetriFilm SEC agar to isolate E. coli . We successfully isolated E. coli from 90.6% of these retail meat samples. We identified the phylogenetic type, antimicrobial susceptibility, and antimicrobial resistance genes prevalence between retail meat isolates ( n  = 89). Phylogenetic type B1 was identified from 70.8% of the retail meat isolates, suggesting that the isolates originated primarily from fecal contamination during meat processing. Tetracycline (TET)-resistant isolates with tetA and/or tetB gene(s) were the most frequently detected (28.1%), followed by ampicillin (AMP) resistance genes with bla TEM (15.7%,) and sulfamethoxazole-trimethoprim (SXT) resistance genes with sul2 (15.7%). No extended-spectrum beta-lactamase-producing isolates were detected. A conjugation assay showed that resistance to AMP, TET, and SXT could be simultaneously transferred to recipients. These findings suggest that antimicrobial-resistant E. coli can easily be transferred from farms to tables from retail meats obtained from roadside butcheries.

Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside the HLA complex, CCL24, STYXL1-SRRM3, and C1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10 -8 ) with sarcoidosis; CCL24 and STYXL1-SRRM3 were novel. The disease-risk alleles in CCL24 and IL23R were associated with reduced CCL24 and IL23R expression, respectively. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression. These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. We speculate that the CCL24 risk allele might be involved in a polarized Th1 response in sarcoidosis, and that POR and IL23R risk alleles may lead to diminished host defense against sarcoidosis pathogens.

We report the case of a 60-year-old Japanese man with a metastatic brain tumor that caused ataxia. As a consequence of resection of a cerebellar tumor, the tumor was diagnosed as a poorly differentiated adenocarcinoma with choriocarcinomatous features. The patient underwent bronchoscopy, leading to a diagnosis of the same histology as the brain tumor. After the administration of first-line chemotherapy and maintenance therapy due to progressive disease, he was given nivolumab and obtained a partial response; however, 11-months later, computed tomography showed tumor progression. Our experience suggests that nivolumab has strong activity, even in patients with a rare form of lung cancer.

Background: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare type of interstitial pneumonia characterized by fibroelastosis. Patients with IPPFE as well as idiopathic interstitial pneumonia often have autoimmune diseases, which sometimes coincide with hypothyroidism (HypoT). However, there have been no reports on the association between IPPFE and HypoT. The purpose of this study was to evaluate the correlation between IPPFE and HypoT. We also examined the pathological features of the thyroid glands from autopsied cases., Methods: Thirteen patients diagnosed with IPPFE from among 255 consecutive cases of idiopathic interstitial pneumonia were included in this study; pertinent data were obtained from our hospital's clinical library. We examined the prevalence of HypoT and compared the clinical, radiological, and pathological features between the patients with and those without HypoT. Histological analyses of the lungs and thyroid glands were performed in 4 and 3 cases, respectively., Results: HypoT was identified in 7 of 13 patients (53.8%). Sex, body mass index, survival time, and laboratory test results were not significantly different between patients with and those without HypoT. Radiological and pathological lung findings were similar between both groups of patients. Thyroid gland histology demonstrated perifollicular or interlobular fibrosis without inflammation in all three cases, including a euthyroid case., Conclusions: Although we only analyzed a small number of IPPFE cases, HypoT was prevalent among all of them. Characteristic fibrosis in the thyroid gland was observed even in a euthyroid case. Therefore, patients with IPPFE may potentially have thyroid gland dysfunction through a common pathogenesis in both organs., (Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: CyberKnife® (CK) is a new, advanced radiotherapy technique. This study aimed to evaluate its efficacy and toxicity in Japanese patients with early-stage primary lung tumor who were medically unfit and inoperable., Methods: This retrospective study investigated patients who received CK treatment for medically inoperable Stage І primary lung tumor at the Japanese Red Cross Medical Center between June 2011 and September 2016. Each patient received a total of 36-48 Gy (median, 43 Gy) administered by CK in 4-5 fractions., Results: Totally, 40 patients (T1a, n = 19; T1b, n = 15; T2a, n = 6) were included. Their median age was 86 (range, 56-95) years. Tracking required the use of fiducial markers in 28 patients and the Xsight Spine Tracking System in 12. The median follow-up was 14.5 (range, 1-51) months. Local recurrence occurred in seven (17.5%) patients. The local progression-free survival rates at 1 and 2 years were 83.9% and 74.0%, respectively. Distant recurrence occurred in regional lymph nodes (n = 5), the lung outside the radiation field (n = 3), and the bone (n = 1). Seven patients died. Overall survival rates at 1 and 2 years were 93.6% and 73.1%, respectively. Radiation pneumonitis was identified in 28 (70%) patients (Grade 1, n = 25; Grade 2, n = 2; Grade 5, n = 1)., Conclusions: CK showed good local control with limited toxicity and could be an alternative treatment modality in medically inoperable patients with Stage І primary lung tumor., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Aims: The lung lesion [immunoglobulin (Ig)G4-L] of IgG4-related disease (IgG4-RD) is a condition that occurs together with IgG4-RD and often mimics the lung lesion [idiopathic multicentric Castleman's disease (iMCD-L)] of idiopathic multicentric Castleman's disease (iMCD). Because no clinical and pathological studies had previously compared features of these diseases, we undertook this comparison with clinical and histological data., Methods and Results: Nine patients had IgG4-L (high levels of serum IgG4 and of IgG4 + cells in lung specimens; typical extrapulmonary manifestations). Fifteen patients had iMCD-L (polyclonal hyperimmunoglobulinaemia, elevated serum interleukin-6 levels and polylymphadenopathy with typical lymphadenopathic lesions). Mean values for age, serum haemoglobin levels and IgG4/IgG ratios were higher in the IgG4-L group and C-reactive protein levels were higher in the iMCD-L group. All IgG4-RD lung lesions showed myxomatous granulation-like fibrosis (active fibrosis), with infiltration of lymphoplasmacytes and scattered eosinophils within the perilymphatic stromal area, such as interlobular septa and pleura with obstructive vasculitis. All 15 lung lesions of iMCD, however, had marked accumulation of polyclonal lymphoplasmacytes in lesions with lymphoid follicles and dense fibrosis, mainly in the alveolar area adjacent to interlobular septa and pleura without obstructive vasculitis., Conclusions: Although both lesions had lymphoplasmacytic infiltration, lung lesions of IgG4-RD were characterized by active fibrosis with eosinophilic infiltration within the perilymphatic stromal area with obstructive vasculitis, whereas lung lesions of iMCD had lymphoplasmacyte proliferating lesions mainly in the alveolar area adjacent to the perilymphatic stromal area. These clinicopathological features may help to differentiate the two diseases., (© 2017 John Wiley & Sons Ltd.)